Background

17-Hydroxylase (17-OH) deficiency syndrome is a rare genetic disorder of steroid biosynthesis that causes decreased production of glucocorticoids and sex steroids and increased synthesis of mineralocorticoid precursors. It is a rare form of congenital adrenal hyperplasia resulting from loss-of-function mutations involving the CYP17 gene.

This syndrome is characterized by both of the following:

Decreased production of glucocorticoids and sex steroids, resulting in sexual infantilism in 46,XX females and ambiguous genitalia in 46,XY males

Increased synthesis of mineralocorticoid precursors, resulting in varying degrees of hypertension and hypokalemia

Patients are usually diagnosed with this condition during an evaluation of delayed puberty, absent secondary sexual characteristics, or primary amenorrhea. Although patients with 17-hydroxylase deficiency are cortisol deficient, they do not typically have adrenal insufficiency or experience adrenal crises. Precursor hormones such as corticosterone are elevated, have glucocorticoid activity, and are adequate to prevent adrenal insufficiency.

At puberty, patients require sex steroid replacement for development of secondary sexual characteristics as well as cyclic menstrual bleeding in 46,XX females.

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Pathophysiology

Anatomically, the adrenal gland can be divided into the following 3 zones:

Zona glomerulosa, which produces predominately mineralocorticoid

Zona fasciculata, which produces predominately glucocorticoid

Zona reticularis, which produces predominately androgens

For convenience, think of the zona glomerulosa as the first endocrine organ and the zonae fasciculata and reticularis collectively as a second separate endocrine organ, as distinguished by distinct control systems.

Aldosterone (mineralocorticoid) synthesis and secretion is regulated via the renin-angiotensin system, which is responsive to the electrolyte balance state and plasma volume. Aldosterone secretion is also directly stimulated by high serum potassium concentrations. In contrast, cortisol synthesis and secretion is regulated by adrenocorticotropic hormone (ACTH), which stimulates the enzyme P-450scc (20, 22 desmolase) with subsequent increased production of all adrenal steroids in both the zona fasciculata and zona reticularis.

Congenital adrenal hyperplasia (CAH) is a family of autosomal recessive disorders of adrenal steroid biosynthesis in which one of the enzymes necessary for cortisol production has deficient activity. Decreased serum cortisol levels stimulate ACTH release via negative feedback. The adrenal glands undergo hypertrophy, apparently due to ACTH-stimulated production of insulinlike growth factor-2 (IGF-2). Increased ACTH secretion also results in overproduction of both the adrenal steroids preceding the missing enzyme and those that do not require the missing enzyme (ie, build-up of compounds both before the block and "sideways" from the block). See following image. Treatment with exogenous glucocorticoid decreases ACTH secretion and subsequent suppression of overproduced steroids.

Representation of typical congenital adrenal hyperplasia (CAH). This example shows a deficiency in both the mineralocorticoid and glucocorticoid pathways. Decreased serum cortisol levels stimulate adrenocorticotropic hormone (ACTH) release via negative feedback. Increased ACTH secretion causes overproduction of adrenal steroids preceding the missing enzyme as well as those not requiring the missing enzyme. The example depicts a deficiency of 21-hydroxylase, resulting in deficient mineralocorticoid and glucocorticoid production and excessive androgen production.

More than 80 different genetic mutations of the CYP17A1 gene have been described worldwide in patients wtih 17-hydroxylase deficiency,
[6] with different mutations occurring more commonly in different populations.
[5, 6, 7, 8, 9, 10] For example, among the Chinese Han, 2 CYP17A1 mutations, D487-S488-F489 deletion and TAC329AA, account for the majority of 17-hydroxylase deficiency cases.
[6] Different CYP17A1 mutations have been found in other Chinese cases, including novel nonsense mutations R449C and L209P.
[7] By contrast, in a Brazilian cohort of 19 families with 17-hydroxylase deficiency,
[8] 7 different CYP17 mutations were found among 24 subjects. However, 2 mutations accounted for most cases: W406R (50%) and R362C (32%). In these families, phenotypic features varied among the subjects and did not correlate with the CYP17 genotype.

A rare cause of 17-hydroxylase deficiency syndrome, first reported in 2004, is autosomal recessive P450 oxidoreductase (POR) deficiency. POR is an obligate electron donor for all microsomal P450 enzymes, including P450c17 (17α-hydroxylase/17,20 lyase), P450c21 (21-hydroxylase) and P450 aro (aromatase). POR deficiency can affect multiple steroidogenic pathways and have variable presentations depending on relative degrees of impaired enzyme activity. Drug metabolism may also be affected in these patients as many drugs are metabolized by hepatic P450s.
[11, 12, 13, 14]

C-17α-hydroxylase is necessary to convert pregnenolone to 17-hydroxypregnenolone (17-OH Preg) and progesterone to 17-hydroxyprogesterone (17-OH Prog); see first image below. Thus, absence of this enzyme impairs all sex steroid and cortisol production (see second image below). Low levels of cortisol result in increased ACTH stimulation of steroids prior to the 17-hydroxylase step, resulting in increased accumulation and secretion of 17-deoxysteroids by the zona fasciculata, including pregnenolone, progesterone, deoxycorticosterone (DOC), and corticosterone (compound B).

C-17α-hydroxylase is necessary to convert pregnenolone to 17-hydroxypregnenolone (17-OH Preg) and progesterone to 17-hydroxyprogesterone (17-OH Prog). Absence of C-17α-hydroxylase impairs all sex steroid and cortisol production. Low levels of cortisol result in increased adrenocorticotropic hormone (ACTH) stimulation of steroids prior to the 17-hydroxylase step, resulting in increased accumulation and secretion of 17-deoxysteroids by the zona fasciculata, including pregnenolone, progesterone, deoxycorticosterone (DOC), and corticosterone.

Epidemiology

Frequency

Approximately 80-90% of individuals with CAH have 21-hydroxylase deficiency. The incidence of classic 21-hydroxylase deficiency varies from 1 in 5,000-15,000 live births in white populations to 1 in 300-700 in the Alaskan Yupik population. Milder (nonclassic) 21-hydroxylase deficiency is estimated to occur in 1 in 1,000 individuals.
[15] The second most common type of CAH, 11-β -hydroxylase deficiency, has an incidence of about 1 in 100,000 individuals (see C-11 Hydroxylase Deficiency). 17-Hydroxylase deficiency is even rarer.

17-Hydroxylase deficiency occurs worldwide. However, as of 2010, only about 130 individuals with severe, confirmed 17-hydroxylase deficiency had been documented,
[16] and most of these reported cases were either isolated or occurred in small clusters. Examples include Turkey, where the reported incidence was 1 in 273 patients with CAH over a 25-year period
[17] ; Brazil, where 16 cases were reported over a 10-year period
[8] ; and Puerto Rico, where 1 case was reported.
[18] . New cases of 17-hydroxylase deficiency continue to be reported,
[9, 10] but the worldwide incidence remains low, especially compared with other forms of CAH.

Age

A diagnosis of 17-hydroxylase deficiency may be suspected in infancy or childhood when hypokalemia and hypertension are found in association with either ambiguous genitalia or in an apparent female patient with a hernia or inguinal mass. However, many patients may go undiagnosed until adolescence or young adulthood. Karyotypic 46,XY patients may be undiagnosed until puberty, having been raised as females, and present to an endocrinologist or nephrologist for evaluation due to lack of secondary sexual characteristics and varying degrees of hypertension and hypokalemia. Similarly, 46,XX patients are usually diagnosed upon presentation of delayed puberty or lack of menses, along with hypertension and hypokalemia.
[16]

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Medical/Legal Pitfalls

Difficulties may arise when this relatively rare diagnosis is not considered, as in the examples described below.

Most patients with 17-hydroxylase (17-OH) deficiency syndrome have some degree of hypertension. Appropriate treatment primarily consists of exogenous glucocorticoid therapy; only more severely affected individuals require antihypertension medications. Failure to reach the proper diagnosis in such a patient may lead to inappropriate or incomplete treatment of the hypertension.

Because patients may appear normal at birth and throughout childhood, female patients may not be diagnosed until they present at a later age with delayed puberty or amenorrhea. Appropriate treatment consists of exogenous sex steroid replacement plus glucocorticoid therapy. Failure to distinguish between 17-hydroxylase deficiency syndrome and other, more common causes of delayed puberty may lead to incomplete treatment.

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Special Concerns

Patients with P450 oxidoreductase deficiency

Because patients with P450 oxidoreductase (POR) deficiency can present with multiple clinical manifestations and have defects in various steroidogenic enzymes, they may be mistakenly diagnosed.
[19] Differentiating 17-hydroxylase deficiency syndrome from POR deficiency is important because patients with POR deficiency have the additional potential for adrenal insufficiency.
[11, 12] POR should be suspected in patients with adrenal insufficiency and genital anomalies who have associated skeletal malformations.

Adults with 17-hydroxylase deficiency

Although extensive literature and experience regarding treatment of pediatric patients is available, little has been published regarding treatment of adults with congenital adrenal hormone deficiencies. Certainly, no consensus or published guidelines are available regarding types, dosages, or timing of steroid replacement in adult patients.
[20, 21]

One survey in the United Kingdom demonstrated that the most widely used glucocorticoid in adult patients was hydrocortisone, followed by dexamethasone and prednisolone. Sixty percent of physicians surveyed used larger doses of glucocorticoids at night (reverse circadian pattern) to achieve adrenocorticotropic hormone (ACTH) suppression, and only 16% of treating physicians used body weight or surface area to determine dosage.

Adult patients must be continuously and carefully treated, using body size or weight-related dosages (in a manner analogous to pediatric treatment) to avoid extremes of overtreatment and undertreatment.

Representation of typical congenital adrenal hyperplasia (CAH). This example shows a deficiency in both the mineralocorticoid and glucocorticoid pathways. Decreased serum cortisol levels stimulate adrenocorticotropic hormone (ACTH) release via negative feedback. Increased ACTH secretion causes overproduction of adrenal steroids preceding the missing enzyme as well as those not requiring the missing enzyme. The example depicts a deficiency of 21-hydroxylase, resulting in deficient mineralocorticoid and glucocorticoid production and excessive androgen production.

C-17α-hydroxylase is necessary to convert pregnenolone to 17-hydroxypregnenolone (17-OH Preg) and progesterone to 17-hydroxyprogesterone (17-OH Prog). Absence of C-17α-hydroxylase impairs all sex steroid and cortisol production. Low levels of cortisol result in increased adrenocorticotropic hormone (ACTH) stimulation of steroids prior to the 17-hydroxylase step, resulting in increased accumulation and secretion of 17-deoxysteroids by the zona fasciculata, including pregnenolone, progesterone, deoxycorticosterone (DOC), and corticosterone.